Islet xenotransplantation from genetically engineered pigs

Current Opinion in Organ Transplantation

Volumn 18, Issue 6, 2013, Pages 695-702

  Nagaraju, Santosh ^a   Bottino, Rita ^b   Wijkstrom, Martin ^a   Hara, Hidetaka ^a   Trucco, Massimo ^b   Cooper, David K C ^a  

^a UNIVERSITY OF PITTSBURGH MEDICAL CENTER   (United States)

^b CHILDREN S HOSPITAL OF PITTSBURGH   (United States)

Author keywords

Diabetes mellitus; Genetically engineered; Islets; Nonhuman primate; Pigs; Xenotransplantation

Indexed keywords

ABATACEPT; ANTIGEN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4 ANTIBODY; DEXTRAN SULFATE; GALACTOSYLTRANSFERASE; GLUCOSE; INSULIN; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; RAPAMYCIN; TACROLIMUS; THYMOCYTE ANTIBODY;

GENETIC ENGINEERING; GLUCOSE METABOLISM; GRAFT FAILURE; GRAFT REJECTION; HUMORAL IMMUNITY; IMMUNE RESPONSE; IMMUNOSUPPRESSIVE TREATMENT; NONHUMAN; PANCREAS ISLET BETA CELL; PANCREAS ISLET TRANSPLANTATION; PRIMATE; REVIEW; SWINE; TRANSGENE; XENOTRANSPLANTATION;

ANIMALS; ANIMALS, GENETICALLY MODIFIED; DIABETES MELLITUS; GLUCOSE; HUMANS; ISLETS OF LANGERHANS TRANSPLANTATION; SWINE; TRANSPLANTATION, HETEROLOGOUS;

EID: 84888305786     PISSN: 10872418     EISSN: 15317013     Source Type: Journal    
DOI: 10.1097/MOT.0000000000000020     Document Type: Review

References (110)

1. Danaei G, Finucane MM, Lu Y, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 2011; 378:31-40.
2. Herman WH. The economic costs of diabetes: is it time for a new treatment paradigm? Diabetes Care 2013; 36:775-776.
3. Center for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States. Atlanta, GA: U.S. Department of Health and Human Services; 2011.
4. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27:1047-1053.
5. Maahs DM, West NA, Lawrence JM, et al. Epidemiology of type 1 diabetes. Endocrinol Metab Clin N Am 2010; 39:481-497.
6. White SA, Shaw JA, Sutherland DE. Pancreas transplantation. Lancet 2009; 373:1808-1817.
7. Kayler LK, Wen X, Zachariah M, et al. Outcomes and survival analysis of oldto-old simultaneous pancreas and kidney transplantation. Transpl Int 2013. doi: 10.1111/tri.12142.; Epub ahead of print.
8. Gruessner AC. Update on pancreas transplantation: comprehensive trend analysis of 25 000 cases followed up over the course of twenty-four years at the International Pancreas Transplant Registry (IPTR). Rev Diabet Stud 2011; 8:6-16.
9. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000; 343:230-238.
10. Barton FB, Rickels MR, Alejandro R, et al. Improvement in outcomes of clinical islet transplantation:. Diabetes Care 2012; 35:1436-1445.
11. Hering BJ, Kandaswamy R, Ansite JD, et al. Single donor, marginal dose islet transplantation in patients with type 1 diabetes. JAMA 2005; 293:830-835.
12. CITR seventh annual report, 30th December 2011[internet] http://www.citregistry.org/. [Accessed on 19 July 2013]
13. Bellin MD, Barton FB, Heitman A, et al. Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant 2012; 12:1576-1583.
14. UNOS data, [internet] http://optn.transplant.hrsa.gov/latestData/rptData. asp. [Accessed on 19 July 2013]
15. Scientific Registry of Transplant Recipients, [internet] http://www.srtr.org/csr/current/NatPublic201206/pdf/PA201206.pdf [Accessed on 19 March 2013].
16. Home PD, Alberti KG. The new insulins. Their characteristics and clinical indications. Drugs 1982; 24:401-413.
17. Sonnenberg GE, Berger M. Human insul much ado about one amino acid? Diabetologia 1983; 25:457-459.
18. Dufrane D, Gianello P. Pig islet for xenotransplantation in human: structural and physiological compatibility for human clinical application. Transplant Rev (Philadelphia) 2012; 26:183-188.
19. Ricordi C, Finke EH, Lacy PE. A method for the mass isolation of islets from adult pig pancreas. Diabetes 1986; 35:649-653.
20. Bertera S, Marigliano M, Bottino R, Trucco M. Pancreatic islet isolation from swine. In: Langer R, Yarmush ML, editors. Methods in Bioengineering, MIT and Harvard Medical School. 2011; Chapter 6, pp. 77-99.
21. Shimoda M, Noguchi H, Fujita Y, et al. Improvement of porcine islet isolation by inhibition of trypsin activity during pancreas preservation and digestion using 1-antitrypsin. Cell Transplant 2012; 21:465-471.
22. Shimoda M, Noguchi H, Fujita Y, et al. Islet purification method using large bottles effectively achieves high islet yield from pig pancreas. Cell Transplant 2012; 21:501-508.
23. Ulrichs K, Eber S, Schneiker B, et al. Isolation of porcine pancreatic islets for xenotransplantation. Methods Mol Biol 2012; 885:213-232.
24. Oshibe I, Saito T, Sato Y, et al. Adenine nucleotide levels in a closed enzymatic digestion system for porcine islet isolation. Cell Transplant 2012; 21:483-491.
25. Zhu H, Yu L, Wang B. Progress in isolation and purification of porcine islets. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2012; 26:1012-1016.
26. Annes JP, Ryu JH, Lam K, et al. Adenosine kinase inhibition selectively promotes rodent and porcine islet-cell replication. Proc Natl Acad Sci U S A 2012; 109:3915-3920.
27. Jiang X, Qian T, Linn T, et al. Islet isolation and purification from inbred wuzhishan miniature pigs. Xenotransplantation 2012; 19:159-165.
28. Kitzmann JP, Law L, Shome A, et al. Real-time assessment of encapsulated neonatal porcine islets prior to clinical xenotransplantation. Xenotransplantation 2012; 19:333-336.
29. Brandhorst H, Iken M, Scott WE 3rd, et al. Quality of isolated pig islets is improved using perfluorohexyloctane for pancreas storage in a split lobe model. Cell Transplant 2013; 22:1477-1483.
30. Mueller KR, Balamurugan AN, Cline GW, et al. Differences in glucosestimulated insulin secretion in vitro of islets from human, nonhuman primate, and porcine origin. Xenotransplantation 2013; 20:75-81.
31. Koulmanda M, Qipo A, Smith RN, et al. Pig islet xenografts are resistant to autoimmune destruction by nonobese diabetic recipients after anti-CD4 treatment. Xenotransplantation 2003; 10:178-184.
32. Groth CG, Korsgren O, Tibell A, et al. Transplantation of porcine fetal pancreas to diabetic patients. Lancet 1994; 344:1402-1404.
33. Elliott RB, Escobar L, Tan PLJ, et al. Live encapsulated porcine islets from a type 1diabetic patient 9.5 yr after xenotransplantation. Xenotransplantation 2007; 14:157-161.
34. Valdes-Gonzalez R, Rodriguez-Ventura AL, White DJ, et al. Long-term followup of patients with type 1 diabetes transplanted with neonatal pig islets. Clin Exp Immunol 2010; 162:537-542.
35. Elliott RB. Towards xenotransplantation of pig islets in the clinic. Curr Opin Organ Transplant 2011; 16:195-200.
36. Elliott RB, Nathu D. Evidence of safety and efficacy of two forms of neonatal cell transplants. Xenotransplantation 2013; 20:49.
37. Sun Y, Ma X, Zhou D, et al. Normalization of diabetes in spontaneously diabetic cynomolgus monkeys by xenografts of microencapsulated porcine islets without immunosuppression. J Clin Invest 1996; 98:1417-1422.
38. Buhler L, Deng S, O'Neil J, et al. Adult porcine islet transplantation in baboons treated with conventional immunosuppression or a nonmyeloablative regimen and CD154 blockade. Xenotransplantation 2002; 9:3-13.
39. Kirchhof N, Shibata S, Wijkstrom M, et al. Reversal of diabetes in nonimmunosuppressed rhesus macaques by intra portal porcine islet xenografts precedes acute cellular rejection. Xenotransplantation 2004; 11:396-407.
40. Elliott RB, Escobar L, Tan PLJ, et al. Intraperitoneal alginate-encapsulated neonatal porcine islets in a placebo-controlled study with 16 diabetic cynomolgus primates. Transplant Proc 2005; 37:3505-3508.
41. Cardona K, Korbutt GS, Milas Z, et al. Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat Med 2006; 12:304-306.
42. Hering BJ, Wijkstrom M, Graham ML, et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat Med 2006; 12:301-303.
43. Cardona K, Milas Z, Strobert E, et al. Engraftment of adult porcine islet xenografts in diabetic nonhuman primates through targeting of costimulation pathways. Am J Transplant 2007; 7:2260-2268.
44. Gianello P, Dufrane D. Encapsulation of pig islets by alginate matrix to correct streptozotocin-induced diabetes in primates without immunosuppression. Xenotransplantation 2007; 14:441.
45. Russell MC, Cardona K, Olivia VL, et al. Engraftment of neonatal porcine islets in diabetic nonhuman primates by blockade of the CD28/CD40 costimulatory pathways. Xenotransplantation 2007; 14:423.
46. Casu A, Bottino R, Balamurugan AN, et al. Metabolic aspects of pig-tomonkey (Macaca fascicularis) islet transplantation: implications for translation into clinical practice. Diabetologia 2008; 51:120-129.
47. Thompson P, Cardona K, Russell M, et al. CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates. Am J Transplant 2011; 11:947-957.
48. van der Windt DJ, Bottino R, Kumar G, et al. Clinical islet xenotransplantation: how close are we? Diabetes 2012; 61:3046-3055.
49. Graham M, Schuurman HJ. The usefulness and limitations of the diabetic macaque model in evaluating long-term porcine islet xenograft survival. Xenotransplantation 2013; 20:5-17.
50. Hecht G, Eventor-Friedman S, Rosen C, et al. Pig embryonic pancreas in diabetic nonhuman primate. Proct National Acad Sci USA 2009; 106:8659-8664.
51. Tchorsh-Yutsis D, Hecht G, Aronovich A, et al. Pig embryonic pancreatic tissue as a source for transplantation in diabetes: transient treatment with anti-LFA1, anti-CD48 and FTY720 enables long term graft maintenance in mice with only mild ongoing immunosuppression. Diabetes 2009; 58:1585-1594.
52. Hammerman MR. Development of a novel xenotransplant strategy for treatment of diabetes mellitus in rat hosts and translation to nonhuman primates. Organogenesis 2012; 8:41-48.
53. Bennet W, Sundberg B, Groth CG, et al. Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation? Diabetes 1999; 48:1907-1914.
54. Cantarovich D, Blancho G, Potiron N, et al. Rapid failure of pig islet transplantation in nonhuman primates. Xenotransplantation 2002; 9:25-35.
55. van der Windt DJ, Bottino R, Casu A, et al. Rapid loss of intraportallytransplanted islets: an overview of pathophysiology and preventive strategies. Xenotransplantation 2007; 14:288-297.
56. Ma X, Ye B, Gao F, et al. Tissue factor knockdown in porcine islets: an effective approach to suppressing the instant blood-mediated inflammatory reaction. Cell Transplant 2012; 21:61-71.
57. Jung YS, Jeong JH, Yook S, et al. Surface modification of pancreatic islets using heparin-DOPA conjugate and anti-CD154 mAb for the prolonged survival of intrahepatic transplanted islets in a xenograft model. Biomaterials 2012; 33:295-303.
58. Luan NM, Iwata H. Xenotransplantation of islets enclosed in agarose microcapsule carrying soluble complement receptor 1. Biomaterials 2012; 33:8075-8081.
59. Bottino R, Fernandez LA, Ricordi C, et al. Transplantation of allogeneic islets of Langerhans in the rat liver: effects of macrophage depletion on graft survival and microenvironment activation. Diabetes 1998; 47:316-323.
60. van der windt DJ, Marigliano M, He J, et al. Early islet damage after direct exposure of pig islets to blood: has humoral immunity been underestimated? Cell Transplant 2012; 21:1791-1802.
61. Kim HI, Yu JE, Lee SY, et al. The effect of composite pig islet-human endothelial cell grafts on the instant blood-mediated inflammatory reaction. Cell Transplant 2009; 18:31-37.
62. Thompson P, Badell IR, Lowe M, et al. Alternative immunomodulatory strategies for xenotransplantation: CD40/154 pathway-sparing regimes promote xenograft survival. Am J Transplant 2012; 12:1765-1775.
63. Ashkenazi E, Baranovski BM, Shahaf G, Lewis EC. Pancreatic islet xenograft survival in mice is extended by a combination of alpha-1-antitrypsin and single-dose anti-CD4/CD8 therapy. PLoS ONE 2013; 8:e63625.
64. Yi S, Ji M, Wu J, et al. Adoptive transfer with in vitro expanded human regulatory T-cells protects against porcine islet xenograft rejection via interleukin- 10 in humanized mice. Diabetes 2012; 61:1180-119165.
65. Yamashita M, Saito T, Ise K, et al. Mizoribine as sole immunosuppressive agent in islet xenotransplantation models: a candidate immunosuppressant causing no adverse effects on islets. Cell Transplant 2012; 21:535-545.
66. Domenech N. Xenoantibodies and complement activity determinations in pig-to-primate xenotransplantation. Methods Mol Biol 2012; 885:57-69.
67. d'Apice JFA, Cowan PJ. Gene-modified pigs. Xenotransplantation 2008; 15:87-90.
68. d'Apice JFA, Cowan PJ. Xenotransplantation: the next generation of engineered animals. Transpl Immunol 2009; 21:111-115.
69. Cooper DK, Dorling A, Pierson RN 3rd, et al. Alpha1,3- galactosyltransferase gene-knockout pigs for xenotransplantation: where do we go from here? Transplantation 2007; 84:1-7.
70. van der Windt DJ, Bottino R, Casu A, et al. Long-term controlled normoglycemia in diabetic nonhuman primates after transplantation with hCD46 transgenic porcine islets. Am J Transplant 2009; 9:2716-2726.
71. Thompson P, Badell IR, Lowe M, et al. Islet xenotransplantation using galdeficient neonatal donors improves engraftment and function. Am J Transplant 2011; 11:2593-2602.
72. Phelps CJ, Koike C, Vaught TD, et al. Production of alpha 1,3 galactosyltransferase-deficient pigs. Science 2003; 299:411-414.
73. Cozzi E, White DJG. The generation of transgenic pigs as potential organ donors for humans. Nat Med 1995; 1:964-969.
74. Ryan EA, Lakey JR, Rajotte RV, et al. Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes 2001; 50:710-719.
75. Teratani T, Matsunari H, Kasahara N, et al. Islets from rats and pigs transgenic for photogenic proteins. Curr Diabetes Rev 2012; 8:382-389.
76. Casu A, Echeverri GJ, Bottino R, et al. Insulin secretion and glucose metabolism in alpha 1,3-galactosyltransferase knock-out pigs compared to wild-type pigs. Xenotransplantation 2010; 17:131-139.
77. Ayares D, Phelps C, Vaught T, et al. Multitransgenic pigs for xenoislet transplantation. Xenotransplantation 2013; 20:39-64.
78. Mandel TE, Koulmanda M, Cozzi E, et al. Transplantation of normal and DAFtransgenic fetal pig pancreas into cynomolgus monkeys. Transplant Proc 1997; 29:940.
79. Komoda H, Miyagawa S, Omori T, et al. Survival of adult islet grafts from transgenic pigs with N-acetylglucosaminyltransferase-III (GnT-III) in cynomolgus monkeys. Xenotransplantation 2005; 12:209-216.
80. Rood PP, Bottino R, Balamurugan AN, et al. Reduction of early graft loss after intraportal porcine islet transplantation in monkeys. Transplantation 2007; 83:202-210.
81. McKenzie IF, Koulmanda M, Mandel TE, Sandrin MS. Pig islet xenografts are susceptible to 'antipig' but not Gal alpha(1,3)Gal antibody plus complement in Gal o/o mice. J Immunol 1998; 161:5116-5119.
82. Rayat GR, Rajotte RV, Hering BJ, et al. In vitro and in vivo expression of Galalpha (1, 3) Gal on porcine islet cells is age dependent. J Endocrinol 2003; 177:127-135.
83. Komoda H, Miyagawa S, Kubo T, et al. A study of the xenoantigenicity of adult pig islets cells. Xenotransplantation 2004; 11:237-346.
84. Omori T, Nishida T, Komoda H, et al. A study of the xenoantigenicity of neonatal porcine islet-like cell clusters (NPCC) and the efficiency of adenovirusmediated DAF (CD55) expression. Xenotransplantation 2006; 13:455-464.
85. Nakatsu S, Takama Y, Ueno T, et al. A study of the glycoantigens of neonatal porcine islet-like cell clusters using a lectin microarray. Transplant Proc 2012; 44:1134-1135.
86. Tanemura M, Miyagawa S, Ihara Y, et al. Significant down regulation of the major swine xenoantigen by N-acetylglucosaminyltransferase III gene transfection. Biochem Biophys Res Commun 1997; 235:359-364.
87. Miyagawa S, Murakami H, Takahagi Y, et al. Remodeling of the major pig xenoantigen by N-acetylglucosaminyltransferase III in transgenic pig. J Biol Chem 2001; 276:39310-39319.
88. Koyota S, Ikeda Y, Miyagawa S, et al. Down-regulation of the alpha-Gal epitope expression in N-glycans of swine endothelial cells by transfection with the N-acetylglucosaminyltransferase III gene: modulation of the biosynthesis of terminal structures by a bisecting GlcNAc. J Biol Chem 2001; 276:32867-32874.
89. Barilla-LaBarca ML, Liszewski MK, Lambris JD, et al. Role of membrane cofactor protein (CD46) in regulation of C4b and C3b deposited on cells. J Immunol 2002; 168:6298-6304.
90. Padler-Karavani V, Varki A. Potential impact of the nonhuman sialic acid N-glycolylneuraminic acid on transplant rejection risk. Xenotransplantation 2011; 18:1-5.
91. Zhu A. Binding of human natural antibodies to non αGal xenoantigens on porcine erythrocytes. Transplantation 2000; 69:2422-2428.
92. Zhu A, Hurst R. Anti-N-glycolylneuraminic acid antibodies identified in healthy human serum. Xenotransplantation 2002; 9:376-381.
93. Park JY, Park MR, Bui HT, et al. 1,3-galactosyltransferase deficiency in germfree miniature pigs increases N-glycolylneuraminic acids as the xenoantigenic determinant in pig-human xenotransplantation. Cell Reprogram 2012; 14:353-363.
94. Lutz AJ, Li P, Estrada JL, et al. Double knockout pigs deficient in N-glycolylneuraminic acid and galactose α-1,3-galactose reduce the humoral barrier to xenotransplantation. Xenotransplantation 2013; 20:27-35.
95. Phelps C, Ball S, Vaught T, et al. Production and characterization of transgenic pigs expressing porcine CTLA4-Ig. Xenotransplantation 2009; 16:477-485.
96. Badin RA, Padoan A, Vadori M, et al. Long-term clinical recovery in parkinsonian monkey recipients of CTLA4-Ig transgenic porcine neural precursors. Transplantation 2010; 90.
97. Lévêque X, Cozzi E, Naveilhan P, Neveu I. Intracerebral xenotransplantation: recent findings and perspectives for local immunosuppression. Curr Opin Organ Transplant 2011; 16:190-194.
98. Klymiuk N, van Beurck L, Bahr A, et al. Xenografted islet cell clusters from insLEA29Y transgenic pigs rescue diabetes and prevent immune rejection in humanized mice. Diabetes 2012; 61:1527-1532.
99. Hara H, Crossley T, Witt W, et al. Dominant-negative CIITA transgenic pigs: effect on the human antipig T cell immune response and immune status. Am J Transplant 2010; 10.
100. Hara H, Witt W, Crossley T, et al. Human dominant-negative class II transactivator transgenic pigs - effect on the human antipig T cell immune response and immune status. Immunology 2013; 136:1-31.
101. Yeom HJ, Koo OJ, Yang J, et al. Generation and characterization of human heme oxygenase-1 transgenic pigs. PLoS ONE 2012; 7: e46646.
102. Ji M, Yi S, Smith-Hurst H, et al. The importance of tissue factor expression by porcine NICC in triggering IBMIR in the xenograft setting. Transplantation 2011; 91:841-846.
103. Denner J, Tonjes RR. Infection barriers to successful xenotransplantation focusing on porcine endogenous retroviruses. Clin Microbiol Rev 2012; 25:318-343.
104. Busby SA, Crossan C, Godwin J, et al. Suggestions for the diagnosis and elimination of hepatitis E virus in pigs used for xenotransplantation. Xenotransplantation 2013; 20:188-192.
105. Onions D, Cooper DKC, Alexander TJL, et al. An assessment of the risk of xenozoonotic disease in pig-to-human xenotransplantation. Xenotransplantation 2000; 7:143-155.
106. Takeuchi Y, Fishman J. Long life with or without PERV. Xenotransplantation 2010; 17:429-430.
107. Semaan M, Rotem A, Barkai U, et al. Screening pigs for xenotransplantation: prevalence and expression of porcine endogenous retroviruses in Gottingen minipigs. Xenotransplantation 2013; 20:148-156.
108. Mattiuzzo G, Takeuchi Y, Scobie L. Potential zoonotic infection of porcine endogenous retrovirus in xenotransplantation. Methods Mol Biol 2012; 885:263-279.
109. Dieckhoff B, Petersen B, Kues WA, et al. Knockdown of porcine endogenous retrovirus (PERV) expression by PERV-specific shRNA in transgenic pigs. Xenotransplantation 2008; 15:36-45.
110. Ramsoondar J, Vaught T, Ball S, et al. Production of transgenic pigs that express porcine endogenous retrovirus small interfering RNAs. Xenotransplantation 2009; 16:164-180.